AUTHOR=Jiao Dong L., Chen Yan , Liu Yao , Ju Yun Y., Long Jian D., Du Jiang , Yu Chang X., Wang Yu J., Zhao Min , Liu Jing G.

TITLE=SYVN1, an ERAD E3 ubiquitin ligase, is involved in GABAAα1 degradation associated with methamphetamine-induced conditioned place preference

JOURNAL=Frontiers in Molecular Neuroscience

VOLUME=10

YEAR=2017

URL=https://www.frontiersin.org/journals/molecular-neuroscience/articles/10.3389/fnmol.2017.00313

DOI=10.3389/fnmol.2017.00313

ISSN=1662-5099

ABSTRACT=<p>Abuse of methamphetamine (METH), a powerful addictive amphetamine-type stimulants (ATS), is becoming a global public health problem. The gamma-aminobutyric acid (GABA)ergic system plays a critical role in METH use disorders. By using rat METH conditioned place preference (CPP) model, we previously demonstrated that METH-associated rewarding memory formation was associated with the reduction of GABA<sub>A</sub>α1 expression in the dorsal straitum (Dstr), however, the underlying mechanism was unclear. In the present study, we found that METH-induced CPP formation was accompanied by a significant increase in the expression of Synovial apoptosis inhibitor 1 (SYVN1), an endoplasmic reticulum (ER)-associated degradation (ERAD) E3 ubiquitin ligase, in the Dstr. The siRNA knockdown of SYVN1 significantly increased GABA<sub>A</sub>α1 protein levels in both primary cultured neurons and rodent Dstr. Inhibition of proteasomal activity by MG132 and Lactacystin significantly increased GABA<sub>A</sub>α1 protein levels. We further found that SYVN1 knockdown increased GABA<sub>A</sub>α1 in the intra-ER, but not in the extra-ER. Accordingly, endoplasmic reticulum stress (ERS)-associated Glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) increased. Thus, this study revealed that SYVN1, as the ERAD E3 ubiquitin ligase, was associated with Dstr GABA<sub>A</sub>α1 degradation induced by METH conditioned pairing.</p>